Identification of a novel SP3 binding site in the promoter of human IGFBP4 gene: role of SP3 and AP-1 in regulating promoter activity in CaCo2 cells

Shen, Qiang; Singh, Pomila

doi:10.1038/sj.onc.1207354

Cited by 8 publications

(7 citation statements)

References 45 publications

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“…These data suggest that downregulation of IGFBP-4 expression in vascular smooth muscle plays a critical role in vascular growth response in normal and diseased states, by increasing the bioavailability of IGF-I (27). In addition to its antiproliferative action, IGFBP-4 has been correlated with differentiation of cancer cells (28).…”

Section: Biological Actions Of Igfbp-4mentioning

confidence: 89%

Biology of insulin-like growth factor binding protein-4 and its role in cancer (review)

Durai

Davies²,

Yang³

et al. 2006

Int J Oncol

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Insulin-like growth factor binding protein-4 (IGFBP-4) is an important member of the insulin-like growth factor (IGF) system. The IGFBP-4 has three domains of which the N-terminal sequence is important for the binding of IGF. It acts as a transport protein for IGF-I and IGF-II and modulates their biological effects. There is increasing evidence that IGFBP-4 inhibits IGF-induced cellular growth both in vitro and in vivo. IGFBP-4 can also mediate its actions through a mechanism independent of IGFs. IGFBP-4 level and expression in various tissues are influenced by IGFBP protease, nutrition, several growth factors and hormones. Overexpression of IGFBP-4 in transgenic animal models causes reduced growth of organs containing smooth muscle. Most cancers express IGFBP-4 at levels which correlate with their state of differentiation. However, the effects of IGFBP-4 on tumor growth are uncertain. In vitro studies have shown that overexpression of IGFBP-4 inhibit the growth of some colon cancer cells. Overexpression of IGFBP-4 in vivo has been reported to decrease the growth of prostate cancer. The effect of altered expression of IGFBP-4 in vivo in colon and other cancers needs to be explored as locally available IGFs appear to stimulate mitogenesis. Contents 1. Introduction 2. Structure and binding characteristics of IGFBP-4 3. Biological actions of IGFBP-4 4. Factors controlling IGFBP-4 expression 5.

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Section: Biological Actions Of Igfbp-4mentioning

confidence: 89%

Biology of insulin-like growth factor binding protein-4 and its role in cancer (review)

Durai

Davies²,

Yang³

et al. 2006

Int J Oncol

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“…In this study, we conducted reporter gene assays using various lengths of IGFBP-4 and IGFBP-2 promoter elements. It has been shown that estrogen receptor-Sp1 complexes 47 or Sp3 (Sp3-binding site: Ϫ861 nucleotides to Ϫ856 nucleotides from the transcription start site) 48 regulates the promoter activity and thus the expression of human IGFBP-4. Our search for putative transcription factor-binding sites yielded two putative sites for thyroid transcription factor 1 (TTF-1), which is specifically expressed in lung airway epithelial cells, in the distal region of the human IGFBP-4 promoter (Ϫ1059 nucleotides to Ϫ1045 nucleotides, and Ϫ922 nucleotides to Ϫ908 nucleotides from the transcription start site).…”

Section: Discussionmentioning

confidence: 99%

Growth Regulation via Insulin-Like Growth Factor Binding Protein-4 and −2 in Association with Mutant K-ras in Lung Epithelia

Sato

Yazawa

Suzuki

et al. 2006

The American Journal of Pathology

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Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes.

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“…In fact, Sp3, does not only act as a repressor, but can also act as a strong transcriptional activator. 61,64,65 With respect to the C4.4A gene, Sp3 clearly functions as an activator and not as a repressor.…”

Section: Discussionmentioning

confidence: 99%

CEBPβ, JunD and c‐Jun contribute to the transcriptional activation of the metastasis‐associated C4.4A gene

Fries

Nazarenko

Heß

et al. 2007

Intl Journal of Cancer

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The glycosylphosphatidylinositol‐anchored molecule C4.4A, which shares structural features with uPAR, is frequently expressed on carcinomas with upregulated expression during tumor progression. Moreover, rare expression on nontransformed epithelial cells is strongly increased during tissue remodeling, e.g., during wound healing. This strictly regulated expression prompted us to define transcriptional activation of the C4.4A gene. C4.4A transcription was analyzed in 2 syngenic rat tumor cell lines with low or high metastatic potential, respectively. Though genomic C4.4A DNA was present in both lines, C4.4A mRNA and transcription of a reporter construct containing the C4.4A promoter was only observed in the metastasizing subline. Deletions and point mutations in the C4.4A promoter‐driven reporter construct revealed that activation of the TATA‐less, GC‐rich core promoter (−1 to −50 bp) does not suffice to initiate transcription that requires coactivation of a proximal response element (−71 to −88 bp) and can be further increased by more distal response elements (−89 to −133 bp). Mobility‐shift and cotransfection studies showed that Sp3 binding enhances C4.4A transcription, whereas potential Sp1 binding sites were ineffective. C4.4A transcription essentially requires C/EBPβ binding to a TRE/CCAAT composite element (−71 to −88 bp) as measured by ChIP assay. C4.4A transcription is strikingly enhanced by cotransfection with JunD or c‐Jun, such that C4.4A is most strongly transcribed even in the C4.4A‐negative tumor cell line after cotransfection with C/EBPβ plus JunD or c‐Jun. Thus, upregulation of C/EBPβ during tumor progression and wound repair may well provide a sufficient trigger for transcription of the C4.4A gene. © 2007 Wiley‐Liss, Inc.

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Identification of a novel SP3 binding site in the promoter of human IGFBP4 gene: role of SP3 and AP-1 in regulating promoter activity in CaCo2 cells

Cited by 8 publications

References 45 publications

Biology of insulin-like growth factor binding protein-4 and its role in cancer (review)

Biology of insulin-like growth factor binding protein-4 and its role in cancer (review)

Growth Regulation via Insulin-Like Growth Factor Binding Protein-4 and −2 in Association with Mutant K-ras in Lung Epithelia

CEBPβ, JunD and c‐Jun contribute to the transcriptional activation of the metastasis‐associated C4.4A gene

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